During times of physiological stress, the human heart is able to markedly increase contractility. This response is facilitated by the release of norepinephrine from postganglionic sympathetic nerves and epinephrine from the adrenal gland. These neurotransmitters effect a contractile response by interacting with a transmembrane signaling system within the myocyte sarcolemma consisting of beta 1- and beta 2-adrenergic receptors, the guanine nucleotide-binding regulatory proteins Gs and Gi, and the effector enzyme adenylyl cyclase. Activation of this beta-receptor-G-protein-adenylyl cyclase signal transduction complex results in production of the second messenger, cAMP, activation of protein kinase A, and phosphorylation of a group of cellular proteins that are important in excitation-contraction coupling. In contrast to normal human myocardium, the failing human heart is insensitive to adrenergic stimulation. This insensitivity is a result of alterations in the function of this signal transduction pathway, including selective downregulation of the beta 1-adrenergic receptor, uncoupling of beta 2-adrenergic receptors from adenylyl cyclase, and an increase in the functional activity of the inhibitory G-protein. Subtle yet important differences exist between beta-adrenergic neuroeffector mechanisms in idiopathic dilated cardiomyopathy and cardiomyopathy secondary to ischemic heart disease. Most notably, beta-receptors are downregulated to a lesser degree in patients with ischemic heart disease. Therefore, various types of end-stage heart muscle disease may exhibit important pathophysiological differences despite common clinical features and an understanding of the regulatory mechanisms that modulate cardiac signal transduction may have therapeutic implications.